Degradation of Biological Products and Impact on Higher Order Structure
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1 Degradation of Biological Products and Impact on Higher Order Jason K. Cheung, BioProcess Development Biologics and Vaccines Date: May 16, 2016 AAPS-NBC Sunrise Session
2 Analytical Toolkit 2
3 Analytical Toolkit 3
4 Conventional methods to characterize higher order Technique Far-UV Circular Dichroism Fourier Transform Infrared (FT-IR) Near-UV Circular Dichroism Fluorescence Spectroscopy Analytical Ultracentrifuge (AUC) Dynamic Light Scattering (DLS) Differential Scanning Calorimetry (DSC) Attribute Secondary Secondary Tertiary Tertiary Thermal Stability / Unfolding Temperatures 4
5 Use of biophysical assays to characterize impurities Impurities could include Amino acid misincorporations, Deamidated species, Dimers, Mis-cleavage, Non-native disulfide bridging, Oxidized Species Main Impurity Impurity
6 MRE Cp MRE Intensity Comparison of HOS of impurity relative to reference Far-UV CD Fluorescence Reference Impurity wavelength (nm) near-uv CD Wavelenth (nm) DSC Wavelength (nm) temperature ( C )
7 MRE Cp MRE Intensity Comparison of HOS of impurity relative to reference Far-UV CD Fluorescence Reference Impurity near-uv CD wavelength (nm) Wavelenth (nm) DSC Wavelength (nm) temperature ( C )
8 HOS and impact on potency Impurity Impurity 1 Impurity 2 Outcome Less active than reference More active than reference MK-1293 Reference Vs. Variant e Concentration ug/ml Reference 4-P Fit: y = (A - D)/( 1 + (x/c)^b ) + D: A B C D R^2 Plot#1 (1_Ref: Concentration vs MeanValue) 3.75e e Plot#2 (1_Variant 1: Concentration vs MeanValue) 3.51e e Impurity 1 8 Weighting: Fixed Reference Impurity 2
9 Newer technologies for characterization Raman Spectroscopy Technique Attribute Far-UV Circular Dichroism Secondary Fourier Transform Infrared (FT-IR) Secondary Raman Spectroscopy Secondary/Tertiary Near-UV Circular Dichroism Tertiary Fluorescence Spectroscopy Tertiary Analytical Ultracentrifuge (AUC) 9 Raman and FT-IR are complementary techniques Raman has stronger amide III signal, whereas IR has stronger amide I signal Dynamic Light Scattering (DLS) Differential Scanning Calorimetry (DSC) Thermal Stability / Unfolding Temperatures
10 Newer technologies for characterization Raman Spectroscopy Normalized Raman Intensity , Cystine Phenyalanine Tyrosine Tryptophan Tyrosine Tryptophan Backbone Phenyalanine Tryptophan Tyrosine Tryptophan Amide III Tryptophan Glutamate Backbone Tryptophan Side chains Amide I Wavenumber (cm -1 ) Malvern Raman and FT-IR are complementary techniques 0 Raman has stronger amide III signal, whereas IR has stronger amide I signal
11 Newer technologies for HOS characterization Raman Optical Activity (BioTools) Differential Raman Scattering of left and right incident and/or scattered radiation Sensitive to the conformational state of a molecule (both structural and stereo sensitivity) Sensitive to folding/unfolding of proteins, different variation of -helix and -sheet, hydration, etc. 1 Thiagarajan et al. J. Raman Spectrosc. 2015, 46,
12 Newer technologies for HOS characterization Initial mab reconstituted to 50 mg/ml and incubated at 50C for 4 wks 1 week Samples characterized neat by ROA Conformational changes observed after 1 week of stress 2 weeks 4 weeks 2 Thiagarajan et al. J. Raman Spectrosc. 2015, 46, S-S stretching Phe/Tyr Amide III Amide I
13 Newer technologies for HOS characterization Zetasizer Helix (Malvern) Allows concurrent measurement of dynamic light scattering and Raman spectroscopy Amenable to high-concentration solutions (>50 mg/ml) Provides size and secondary/tertiary structural information Technique Far-UV Circular Dichroism Fourier Transform Infrared (FT-IR) Raman Spectroscopy Near-UV Circular Dichroism Fluorescence Spectroscopy Analytical Ultracentrifuge (AUC) Dynamic Light Scattering (DLS) Differential Scanning Calorimetry (DSC) Attribute Secondary Secondary Secondary/Tertiary Tertiary Tertiary Thermal Stability / Unfolding Temperatures 3
14 Z-average dia (nm) Newer technologies for HOS characterization mab isothermal incubation Initial Final S-S Tyr Tyr, Trp Amide I Trp ,000 1,200 1,400 1,600 Raman Shift (cm -1 ) Time (min)
15 Z-average dia (nm) Newer technologies for HOS characterization mab thermal denaturation Initial Final ,000 1,100 1,200 1,300 1,400 1,500 1,600 1,700 Raman Shift (cm -1 ) Temperature ( C)
16 Tyr (~857 cm -1 ) Band Position Trp Band Position (Indole Ring Angle) (cm -1 ) Newer technologies for HOS characterization mab thermal denaturation Tm1: 64.3 C Transition1 H: 717 kj/mol Temperature ( C) Tm1: 64.7 C Transition1 H: 605 kj/mol Temperature ( C) 6
17 Biophysical methods to detect fibrils Stabilizers Air-liquid interface Agitation (low ph and elevated temperatures) Technique Far-UV Circular Dichroism Fourier Transform Infrared (FT-IR) Near-UV Circular Dichroism Fluorescence Spectroscopy Analytical Ultracentrifuge (AUC) Dynamic Light Scattering (DLS) Differential Scanning Calorimetry (DSC) Attribute Secondary Secondary Tertiary Tertiary Thermal Stability / Unfolding Temperatures 7 Chiti, F., et al, Proc. Natl. Acad. Sci. 1999, 96, ; Jansen, R., et al, Biophys. J. 2005, 88,
18 ThT Intensity [au] Conventional methods to characterize fibrils Blank mcg/ml 9.2 mcg/ml Technique Far-UV Circular Dichroism Fourier Transform Infrared (FT-IR) Near-UV Circular Dichroism Fluorescence Spectroscopy Analytical Ultracentrifuge (AUC) Dynamic Light Scattering (DLS) Differential Scanning Calorimetry (DSC) Attribute Secondary Secondary Tertiary Tertiary Thermal Stability / Unfolding Temperatures 8
19 Conventional methods to characterize fibrils Wavelength (nm) Far UV-CD shows difference between fibrillated sample ( -sheet) and monomeric sample (α-helix) t=48h t=0 100 ug/ml fibril 1 mg/ml monomer Technique Far-UV Circular Dichroism Fourier Transform Infrared (FT-IR) Near-UV Circular Dichroism Fluorescence Spectroscopy Analytical Ultracentrifuge (AUC) Dynamic Light Scattering (DLS) Differential Scanning Calorimetry (DSC) Attribute Secondary Secondary Tertiary Tertiary Thermal Stability / Unfolding Temperatures Wavenumber (cm-1) 1600 FTIR shows an increase in ( -sheet) as fibrils are formed 1580
20 Conventional methods to characterize fibrils: FTIR ATR is a measurement method to determine FTIR spectrum for insoluble aggregates Monitoring (amide I region) for alpha and beta content Beta sheet Fibril precursor Alpha helical 0 As fibril precursors and fibrils for alpha content decreases, with a concomitant increase in beta content Ahmad et al. J. Biol. Chem. 2005;280:
21 Alternative methods to characterize fibrils Able to produce data on size distributions of a sample, as well as percent of that distribution which is Fluorescence positive Generates side and forward light scattering data. Generates ThT fluorescence data Side scattering = dense aggregation Forward scattering = linear Technique Far-UV Circular Dichroism Fourier Transform Infrared (FT-IR) Near-UV Circular Dichroism Fluorescence Spectroscopy Analytical Ultracentrifuge (AUC) Dynamic Light Scattering (DLS) Differential Scanning Calorimetry (DSC) Imaging (AFM, TEM) Flow Cytometry Attribute Secondary Secondary Tertiary Tertiary Thermal Stability / Unfolding Temperatures 1
22 ThT Intensity [au] Use of flow cytometry to detect fibrils ThT Fluorescence RHI monomer ThT signal (~3) ThT positive cells: 0.05% Increase in ThT fluorescence suggests the presence of fibrils RHI stressed ThT signal (~380) ThT positive cells: 83% 20 Blank mcg/ml 9.2 mcg/ml
23 Use of flow cytometry to detect fibrils ThT Fluorescence Scatter RHI monomer SSC vs FSC pattern suggest the presence of fibrils Fibril Non-Fibril RHI stressed Wall and Solomon. Meth. Enzymology (1999) 23
24 Use of flow cytometry to detect fibrils ThT Fluorescence RHI monomer Scatter TEM RHI stressed 24
25 Example use of Flow Cytometry: Insulin Degludec Agitation of Insulin Degludec for 16 days Increase in ThT fluorescence = fibrils? 25
26 Example use of Flow Cytometry: Insulin Degludec Agitation of Insulin Degludec for 16 days Increase in ThT fluorescence = fibrils? 26
27 Example use of Flow Cytometry: Insulin Degludec Agitation of Insulin Degludec for 16 days Increase in ThT fluorescence = fibrils? Flow cytometry SSC vs FSC suggests amorphous aggregation Initial 16 days 27
28 Expanding toolkit for higher order characterization Technique Attribute 28 Far-UV Circular Dichroism Fourier Transform Infrared (FT-IR) Raman/ROA Spectroscopy Near-UV Circular Dichroism Fluorescence Spectroscopy Analytical Ultracentrifuge (AUC) Dynamic Light Scattering (DLS) Differential Scanning Calorimetry (DSC) Imaging (AFM, TEM) Flow Cytometry Secondary Secondary Secondary/Tertiary Tertiary Tertiary Thermal Stability / Unfolding Temperatures
29 Acknowledgements Example 1 Andrew Semple Huy Pham Sarita Mittal Doug Watson David Wylie Example 3 Malvern (Wei Qi, Neil Lewis, Jeff Hall) Jose James Andrew Semple Geetha Thiagarajan Example 2 Applied BioTools (Rina Dukor) Jun Hyuk Heo Xiadun Mou Effendi Widjaja Busolo Wabuyele Geetha Thiagarajan Example 4 Gayatri Ganesan Andrew Semple Moumita Bhattacharya Geetha Thiagarajan General AAPS NBC Sunrise Session Organizers (Jianmei Kochling and Zhenyu Wang) Mohammed Shameem Soundara Soundararajan Shara Dellatore 29
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